MicroRNA-149 Inhibits Proliferation and Cell Cycle Progression through the Targeting of ZBTB2 in Human Gastric Cancer

Abstract

An increasing body of evidence indicates that miR-149 can both suppress and promote tumor growth depending on the tumor type. However, the role of miR-149 in the progression of gastric cancer (GC) remains unknown. Here we report that miR-149 is a tumor suppressor in human gastric cancer. miR-149 expression is decreased in GC cell lines and clinical specimens in comparison to normal gastric epithelial cell and tissues, respectively. The expression levels of miR-149 also correlate with the differentiation degree of GC cells and tissues. Moreover, ectopic expression of miR-149 in gastric cancer cells inhibits proliferation and cell cycle progression by down-regulating ZBTB2, a potent repressor of the ARF-HDM2-p53-p21 pathway, with a potential binding site for miR-149 in its mRNA's 3′UTR. It is also found that ZBTB2 expression increases in GC cells and tissues compared to normal gastric epithelial cell and tissues, respectively. Silencing of ZBTB2 leads to suppression of cell growth and cell cycle arrest in G0/G1 phase, indicating that ZBTB2 may act as an oncogene in GC. Furthermore, transfection of miR-149 mimics into gastric cancer cells induces down-regulation of ZBTB2 and HDM2, and up-regulation of ARF, p53, and p21 compared to the controls. In summary, our data suggest that miR-149 functions as a tumor suppressor in human gastric cancer by, at least partially through, targeting ZBTB2.

MicroRNA-149 targets specificity protein 1 to suppress human tongue squamous cell carcinoma cell proliferation and motility

“…miRNA is thereby a potential diagnostic and prognostic marker of TSCC with therapeutic potential (18)(19)(20). Previous studies revealed that miR-149 was downregulated in colorectal cancer, breast cancer, gastric cancer, glioma, melanoma and non-small cell lung cancer (21)(22)(23)(24)(25)(26). This study investigated the expression, biological functions and molecular mechanisms of miR-149 in TSCC.…”

“…In addition, miR-149 was reported to decrease glioma cell growth and invasion through targeting protein kinase B signaling (24). Furthermore, Wang et al (23) found that miR-149 suppressed cell proliferation and cell cycle progression via the blockade of zinc finger and BTB domain containing 2 in human gastric cancer. At present, little is known with respect to the role of miR-149 in TSCC.…”

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation

“…31 Ectopic expression of miR-149-5p in gastric cancer cells inhibits proliferation and cell cycle progression. 29 Furthermore, the expression of miR-149-5p was previously demonstrated to have inverse correlation with the invasive capability and epithelial-to-mesenchymal transition of the NSCLC cells. The ectopic transfection of miR-149-5p increases E-cadherin expression.…”

“…Notably, miR-149-5p promotes cell proliferation. 27 Recent study revealed that miR-149-5p expression is significantly downregulated and plays an important role as a tumor suppressor 28 in some cancers, such as gastric cancer, 29 astrocytomas, 30 glioma, 31 colon, and rectum carcinoma (colorectal cancer (CRC)). 32 Overexpression of miR-149-5p was found to inhibit the viability and invasion of cells in vitro and have prognostic and therapeutic implications on CRC.…”

Association of miR-149C>T and miR-499A>G polymorphisms with the risk of hepatocellular carcinoma in the Chinese population

“…MiR-149C>T polymorphisms have been widely investigated in various cancers, such as gastric cancer, lung cancer, colorectal cancer, nasopharyngeal carcinoma, and breast cancer (Luo et al, 2012;Wang et al, 2012;Øster et al, 2013;Wilting et al, 2013;Zhang et al, 2013). Two studies reported that miRNA-149C>T polymorphisms are associated with the development of HCC (Liu et al, 2010;Kim et al, 2012).…”